Cancer is a leading cause of death worldwide. According to statistics, 12 million people are diagnosed with cancer worldwide each year and 7.6 million people died as a result of cancer in 2008 (around 13% of all deaths). In 2010, it is reported on World Cancer Day that cancer accounts for an eighth of all death cases worldwide each year. Currently, in China there is between 1.8 million and 2 million incidence cases of cancer and between 1.4 million and 1.5 million cancer deaths annually.
Functional disorder of protein tyrosine kinases leads to a series of disease in living organisms. Data show that over 50% of proto-oncogenes and ocogene products have protein tyrosine kinase activity, and their abnormal expression would cause the disorder of the regulation of cell proliferation, and further leads to tumorigenesis. Furthermore, the abnormal expression of tyrosine kinases is also closely related to tumor invasion and metastasis, tumor angiogenesis, tumor resistance to chemotherapy. Effective inhibition of protein tyrosine kinases can achieve the purpose of tumor treatment. Protein tyrosine kinases have become a new target for anti-tumor medicant research. Protein tyrosine kinases can be divided into receptor protein tyrosine kinases (RPTKs) and non-receptor protein tyrosine kinases (nRPTKs). RPTKs are typically composed of an extracellular region, a transmembrane region, and an intracellular kinase region. According to the different structures of the extracellular region, RPTKs can be divided into the following main categories: (1) epidermal growth factor receptor (EGFR) family, the main members of the family including EGFR (HER1/erbB-1), HER2 (neu/erbB-2), HER3 (erbB-3), HER4 (erbB-4). The expression of human epidermal growth factor receptors (HERs) is enhanced in many tumors, such as colorectal cancer, head and neck squamous epithelial cell carcinoma, non-small cell lung cancer (NSCLC), breast cancer, pancreatic cancer, renal cell carcinoma; (2) vascular endothelial growth factor receptor (VEGFR), the main members of the family including VEGFR-1 (FLT-1), VEGFR-2 (KDR-FLK-1), VEGFR-3 (FLT-4), etc., which are important regulators in physiological or pathological angiogenesis; (3) platelet-derived growth factor receptor (PDGFR), the main members of the family including PDGFR-α, PDGFR-β, colony-stimulating factor 1 receptor (CSF-1R), FLK-2, stem cell factor receptor (c-kit), etc. Activation of the receptors is associated with tumors; (4) fibroblast growth factor receptor (FGFR), the main members of the family including FGFR-1, FGFR-2, FGFR-3, FGFR-4, etc. Such receptors are closely related to angiogenesis and tumorigenesis; (5) others, such as insulin receptor (INSR), hepatic cell growth factor receptor (HGFG), nerve growth factor receptor (HGFG), etc. (Jian Ding, “Protein tyrosine kinase—a promising anti-tumor target”, Proceedings of the 3th Chinese Conference on Oncology, 2004, 11, 130-140). nRPTKs generally have no extracellular structure. They are usually coupled with cell membranes or present in cytoplasm, such as Src kinase family including Abl, Abl-Brc, etc. The activation of this large category of kinases frequently facilitate the development and progression of tumors. Various tyrosine kinases constitue intersectant and complex cellular signal transduction pathways, and the inhibition of the activity of a tyrosine kinase can often be compensated by the enhancement of the activity of one or more other kinases. Simultaneous inhibition of the activity of multiple tyrosine kinases is a new trend in the current development of this kind of anti-tumor medicaments.
Research has found that aberrant protein tyrosine kinase activity is also associated with other diseases, for example: psoriasis (Dvir, et al., Journal of Cell Biology, 1991, 113, 856-865), fibroid degeneration, atherosclerosis, restenosis (Buchdunger, et al., Proc. Natl. Acad. Sci. USA, 1991, 92, 2258-2262), autoimmune diseases, allergies, asthma, transplant rejection (Klauser and Samelson, Cell, 1991, 64, 875-878), inflammation (Berkois, Blood, 1992, 79(9), 2446-2454), thrombogenesis (Salari, et al., FEBS, 1990, 263(1), 104-108) and nervous system diseases (Ohmichi, et al., Biochemistry, 1992, 31, 4034-4039).
Therefore, it is undoubtedly and extremely advantageous in the treatment of tumor growth, proliferation and other related diseases to choose medicaments, which be able to effectively inhibit overactivity and/or overexpression of tyrosine kinases. Currently, a new class of anti-tumor medicaments acting on tyrosine kinases include imatinib mesylate, gefitinib, erlotinib, sorafenib, dasatinib, lapatinib, and so on.